Eoganacht wrote: Clinical Trials Success Marred with 90% of Disappointment Vera Madzarevic, PhD.
Expert advisor, Science and Clinical Development
Published Mar 16, 2018
It’s been long said that the clinical trial process is costly and cumbersome and that regulatory requirements are too stringent to permit success in bringing a therapeutic product to the market. On the other hand, who would invest in an enterprise that has evidently demonstrated to fail in more than 90% of the cases? Well, large pharma companies as well as thousands of small start-ups are not deterred by the success rate. The rewards on having only one product reach the market, encourages risky investments that in the long term may yield great benefit.
The truth of the matter is that the process to determine the probability of success (POS) is contingent to access to accurate data and risk analysis. Accuracy of the data available to determine risk and POS lays on the knowledge base accrued during preclinical development, as well as having a robust knowledge of the disease and the intricate molecular basis of the disease in question. Further, an in-depth risk assessment will only provide an estimation of success based on previous experiences, and do not contemplate unknown risks that at the end are the most likely reason of failure.
Presently, risk assessments are embedded in the clinical trial process in a manner never seen before, where the new ICG GCP revision 2 prompts sponsors in assessing risk and managing risk during the entire process in a very well documented manner. Needless to say that risk assessments together with stringent requirements for quality assurance will only increase uncertainty.
But where I am heading to?
I want to rationalize why the success rates are so low in comparison with the investment and accrued knowledge to date. A paper published by A. W. Low et al. (2018) makes reason of success rates in drug development.
According to that paper, the overall POS from phase 1 to approval (1-APP) of the 15,102 drugs analyzed between years 2000-2016, phase to phase, is 6.9% for all indications analyzed, while for phase 3 to approval is 59%. Oncology drugs fare the worst with an overall POS of 3.4% (SE,0.2), while cardiovascular and vaccines fare the best with around 25% POS. Also, they demonstrated that the inclusion of biomarkers in clinical trials, increased the POS by almost 50% overall. When they analysed orphan drug development, they observed a similar tendency in POS. The authors also demonstrated that the POS did not change dramatically from year to year for the periods and diseases studied (actually, there was a decrease in the periods between 2007-2010 mostly due in my opinion, to the global economic downfall). However, they observed an increase of POS by almost half, for phase 3 studies in the period of 2014-2015, but with little overall impact.
the overall POS from phase 1 to approval (1-APP) of the 15,102 drugs analyzed between years 2000-2016, phase to phase, is 6.9% for all indications
This paper definitively demonstrates that the POS of clinical trials is low compared to other business endeavours, and that overall we are well below 10% success overall in a phase 1 to APP analysis up to 2015.
The reasons are very varied, and the data only depicts a reality that we are very well aware of, that the drug development process is very volatile, and that some improvements have been observed, but mainly in including study subjects that are considered, due to the use of biomarkers, to be the best candidates to favourably respond to treatment. Of course, that may not extrapolate to changes in prescription habits since the use of biomarkers is very limited.
the inclusion of biomarkers in clinical trials, increased the POS by almost 50% overall
It is very important to understand that the drug development process is extremely complex, since it is based on fundamental challenges of human nature, and that new candidates are only identified in function of marketability and revenues (ROI).
more resources and investments are not translated into new drugs
It is time to implement a new paradigm in clinical research, where candidates are identified and pursue through development based on the very principles of beneficence, ethics and patient safety. Also, it is important to understand that more resources and investments are not translated into new drugs (i.e. oncology drug development), and that depending on the point of view of success, we may not really have great drugs, but just good enough.